Fatigue is one of the most common debilitating symptoms reported by persons with multiple sclerosis (MS). It reflects feelings of tiredness, lack of energy, low motivation, and difficulty in concentrating. It can be measured at a specific instant in time as a perception that arises from interoceptive networks involved in the regulation of homeostasis. Such ratings indicate the state level of fatigue and likely reflect an inability to correct deviations from a balanced homeostatic state. In contrast, the trait level of fatigue is quantified in terms of work capacity (fatigability), which can be either estimated (perceived fatigability) or measured (objective fatigability). Clinically, fatigue is most often quantified with questionnaires that require respondents to estimate their past capacity to perform several cognitive, physical, and psychosocial tasks. These retrospective estimates provide a measure of perceived fatigability. In contrast, the change in an outcome variable during the actual performance of a task provides an objective measure of fatigability. Perceived and objective fatigability do not assess the same underlying construct. Persons with MS who report elevated trait levels of fatigue exhibit deficits in interoceptive networks (insula and dorsal anterior cingulate cortex), including increased functional connectivity during challenging tasks. The state and trait levels of fatigue reported by an individual can be modulated by reward and pain pathways. Understanding the distinction between fatigue and fatigability is critical for the development of effective strategies to reduce the burden of the symptom for individuals with MS.